Hepatitis C virus NS5B RNA-directed RNA polymerase (NS5B) (HCV NS5B polymerase)

Hepatitis C virus NS5B RNA-directed RNA polymerase is the essential catalytic subunit of the viral replicase complex, responsible for the replication of the HCV RNA genome [1, 13]. It functions by using the positive-sense viral RNA as a template to synthesize a negative-strand intermediate, which then serves as a template for the production of numerous progeny positive-strand RNA molecules [1, 15]. Structurally, the enzyme adopts a classic right-hand fold consisting of fingers, palm, and thumb domains, with a unique closed conformation that allows for de novo initiation of RNA synthesis [5, 8, 9]. Because humans lack a direct homolog of this RNA-dependent RNA polymerase, it is a highly attractive and successful target for direct-acting antiviral (DAA) therapy [11, 13, 14]. Drugs targeting NS5B include nucleoside analogs that cause chain termination and non-nucleoside inhibitors that bind to allosteric sites to disrupt enzymatic function [3, 7, 12]. These therapies have revolutionized the treatment of chronic hepatitis C, leading to high cure rates, although challenges such as viral resistance and genotype-specific sensitivity remain [3, 16, 18].

Other names

NS5BNonstructural protein 5BRNA-dependent RNA polymeraseRdRpHCV RdRpHepatitis C virus RNA-directed RNA polymerase

Drugs targeting this enzyme are classified into nucleoside/nucleotide inhibitors (NIs) and non-nucleoside inhibitors (NNIs). NIs, such as sofosbuvir, act as substrate mimics that are incorporated into the nascent RNA strand, leading to premature chain termination [3, 7, 12]. NNIs, such as dasabuvir, bind to allosteric sites on the enzyme (thumb or palm domains), inducing conformational changes that inhibit polymerase activity without competing with natural nucleotides [3, 9, 10, 12].